The present invention relates to a compound represented by general formula A, which is useful as intermediate at the total synthesis of vindoline, 
(in the formula, R1 is one selected from the group consisting of H, OH, alkoxy group, substituted or non-substituted benzenesulfonyloxy group, and alkylsulfonyloxy group, R2 is 1,1-dimethylethoxycarbonyl [(1,1-Dimethylethoxy)carbonyl, Boc] group or acetyl group, R3 is alkyl group, R4 is benzyl or substituted benzyl group. R5 is H, tetrahydropyranyl (THP) group, ethoxyethyl group, methoxymethyl group, acetyl group, benzoyl group, trialkylsilyl group or alkyldiarylsilyl group.), alkyl acrylates represented by general formula B, which is important an intermediate at the total synthesis of vindoline, 
[in the formula, R1 is one selected from the group consisting of H, OH, alkoxy group, substituted or non-substituted benzene sulfonyloxy group, and alkyl sulfonyloxy group, R2 is 1,1-dimethylethoxycarbonyl (indicated as Boc in a constitutional formula) group or acetyl group and, R3 is alkyl group. R5 is H, tetrahydropiranyl (THP) group, ethoxyethyl group, methoxymethyl group, acetyl group, benzoyl group, trialkylsilyl group or alkyldiarylsilyl group.], especially relates to an effective method for synthesis of indole derivatives possessing a methyl acrylate group having good reproducibility and suited to mass production, and an effective method for production of substituted quinolines represented by general formula C, which is useful for the synthesis of said general formula A, and whose regioselectivity and yield are improved. 
(R1, R2 and R3 are independently selected from the group consisting of H, OH, alkoxy group, alkyl, amino, amide and halogen.)
Natural vinblastine (1) extracted from a plant belonging to Apocynaciae is an antitumor agent which is currently used as a clinical medicine. However, since this agent shows a strong side effects, the developments for a new congeners are broadly carried out in Japan or outside of Japan. 
The inventors of the present invention has already reported the art referring to the total synthesis of vindoline which consists a half (lower side) of vinblastine (1) used for the synthesis of above mentioned vinblastine and its congeners. However, for the total synthesis of vindoline, syntheses of various intermediates are necessary, the improvements of the reproducibility of each processes and yield are needed, and the further improvement for process suited to the production concerning the commercial scale is needed.
Usually, the compound represented by said general formula B, which is the important intermediate for the synthesis of vindoline, was synthesized using the derivatives of above mentioned general formula A, whose substituent at 2-position is replaced with iodine, as the starting material by palladium-catalyzed coupling reaction with tin compound as shown in the following Schema 1 [S. Kobayashi, T. Ueda, T. Fukuyama, Synlett., 883-886 (2000)]. 
However, by above mentioned reaction, it is difficult to accomplish the reaction in good yield and with good reproducibility, and further, in above mentioned reaction, there is a problem that the uses of agents such as toxic arsenic compound or carcinogeic hexamethyltriamidephosphate (HMPA) are necessary. Therefore, the establishment of the method for synthesis of above mentioned intermediate B characterizing not including above mentioned technical problems was desired. Further, as one intermediate for the synthesis of above mentioned intermediate A, quinolines represented by general formula C, namely, substituted quinoline which has a substituted group on benzene ring and does not have a substituted group on pyridine ring is used. As the typical well-known method for synthesis for a substituted quinoline which has a substituted group on benzene ring, a method for synthesis named Skraup quinoline synthesis which obtains quinoline by heating anilines, glycerin and oxidant under the presence of strong acid such as sulfuric acid can be mentioned [R. H. F. Manske, M. Kulka, Org. React. 28, 59-98 (1953)]. However, since said method needs a process to react by high temperature using strong acid, many byproducts are generated besides the aimed compound. Therefore, very complicated separation and purification process is necessary to obtain the aimed product and the yield by said method is not always good. Further, in a synthetic reaction of substituted quinoline which uses meta substituted aniline or 2,3-disubstituted aniline as a starting material, mixture of 5-substituted quinoline and 7-substituted quinoline, or mixture of 6,7-substituted quinoline and 5,6-substituted quinoline, which are regioisomers are generated. In the case of said mixture, sometimes one isomer has predominant over another isomer at the generation by maximum four times amount according to the substitution effect, however, in general, the regioselectivity of the reaction is not so high, and this point is pointed out as a problem [M. H. Palmer, J. Chem. Soc., 3645-3652 (1962)]. Still more, the yield is also not so good.
Furthermore, the compound represented by above mentioned general formula C is the compound used as the synthetic intermediate of general formula A, which are the intermediate at the total synthesis of vindoline. And, for the establishment of effective synthetic process for the total synthesis of vindoline, the improvement of the intermediate processes composing total synthesis is very important. Especially, the establishment of the method producing substituted quinolines, which have a substituted group on benzene ring alone and do not have a substituted group on pyridine ring, with improved regioselectivity has been strongly desired.
Therefore, the first object of the present invention is to provide a method for production of the intermediate B represented by general formula B, which dissolves the problem of above mentioned conventional art has, having good yield and reproducibility, and further, said method should be applicable to the production process of commercial scale. The inventors of the present invention have conducted an eager study to investigate the method for production of the compound represented by general formula B not by way of 2-iodoindole shown in the conventional art, and to establish the method for production by way of compound represented by general formula A. Thus the first object of the present invention is accomplished.
The second object of the present invention is to provide a method for the production of substituted quinolines by which the problems in conventional method for production of substituted quinolines have are improved. The inventors of the present invention have investigated the case to obtain the aimed compound represented by general formula C from substituted aniline by way of cyclization reaction, and have found out that the regioselectivity and the yield can be remarkably improved by using following process. Namely, as the first, sulfonamide derivative of above mentioned substituted aniline is prepared, then acrolein is added and a precursor for cyclization reaction is prepared and the precursor is used. The second object of the present invention is accomplished by use of the compound represented by general formula D at the cyclization reaction. 
The first one of the present invention is the compound represented by general formula A which is useful as the intermediate at the total synthesis of vindoline.
The second one of the present invention is a method for synthesis of indole derivatives which are useful for the synthesis of vindoline represented by general formula B comprising, hydrogenation of the compound represented by general formula A, transforming benzyl ester to carboxylic acid, then formation of an acrylic acid alkyl ester unit by Mannich reaction accompanied by decarboxylation under the condition of Mannich reaction. Desirably, the second one of the present invention is the method for synthesis of indole derivatives which are useful for the synthesis of vindoline represented by general formula B comprising, using a palladium on carbon catalyst prepared by loading palladium on activated carbon as a hydrogenation catalyst.
The third one of the present invention is a method for synthesis of the substituted quinolines represented by above mentioned general formula C by reacting substituted aniline sulfonamide compounds represented by general formula E, 
(wherein R1, R2 and R3 is selected independently from the group consisting of H, OH, alkoxy group, alkyl group, amino group and halogen, R4 is an alkyl group such as methyl group or substituted benzene, for example, p-tolyl group) in alcohol containing acrolein and triethylamine so as to synthesize aldehyde intermediate represented by general formula D, then cyclizating said aldehyde intermediate by trifluoromethanesulfonic acid [TfOH: CF3(SO2)OH] or under the acidic condition (acidification by hydrochloric acid or sulfuric acid) and obtaining dihydroquinoline derivatives represented by general formula F, 
then treating the obtained dihydroquinoline derivative in MOH (M is Na or K) in DMSO, and obtaining the substituted quiloline represented by general formula C. Desirably, R1 is a substitution group of 7-position and R2 is a substitution group of 6-position, and each substituted group is respectively selected from the group consisting of H, hydroxyl group, alkoxy group and halogen independently and R3 is H. Further, more desirably, the present invention is the method for synthesis of said substituted quinoline, wherein the cyclization reaction is carried out in tetrahydrofuran solution in which hydrochloric acid of stronger than 3N is contained.
The present invention will be illustrated more in detail.
1-1. At the first, the preparation example of the starting compound represented by general formula A is shown.
In said general formula A, the compound of R1xe2x95x90MsO, R2xe2x95x90Boc, R3xe2x95x90Me, R4xe2x95x90Bn and R5xe2x95x90THP can be effectively synthesized by using quinoline derivative whose hydrogen of hydroxyl group located on 7-position is substituted by alkylsulfonyl group or arylsulfonyl group as a starting material. For example, phenylisothiocyanate having xcex1,xcex2-unsaturated aldehyde is obtained by ring-opening reaction (THF/H2O mixed solution of Na2CO3) of 7-mesyloxyquinoline with thiophosgene (CSCl2) and aldehyde is reduced to alcohol and protected. Then thioamide compound is synthesized by nucleophilic addition reaction of derivatives of malonic acid (in tetrahydrofuran solution of NaH, benzylmethyl malonate is cooled by ice-bath), and the obtained thioamide compound is reacted (in the argon atmosphere) at the temperature of 80xc2x0 C. in toluene solution of tri-n-butyltin hydride (n-Bu3SnH) and 2,2xe2x80x2-azobisisobutyronitrile (AIBN). After cooled down to room temperature, saturated KF solution is added and the resulted mixture was stirred at room temperature, and then diluted with ethyl acetate. After washing with brine, organic layer is dried over magnesium sulfate anhydride and solvent is removed by vacuum. Then the residue is subjected to a silica gel column chromatography and by elution with n-hexane:ethylacetate=2:1 mixed solvent, thus indole derivative compound 1 is obtained. 
1-2. The dichloromethane solution of said compound, di-t-butyl dicarbonate, and triethylamine is cooled with ice-bath and 4-(dimethylamino)pyridine is added, then the temperature is elevated to the room temperature and stirred for 1 hour. The reaction mixture is diluted by ethyl acetate. After washing with brine, organic layer is dried over magnesium sulfate anhydride and solvent is removed by vacuum. Then the residue is subjected to a silica gel column chromatography and by elution with n-hexane:ethylacetate=2:1 mixed solvent, thus the starting material compound of general formula A, especially the starting material characterizing R1xe2x95x90MsO, R2xe2x95x90Boc, R3xe2x95x90Me, R4xe2x95x90Bn and R5xe2x95x90THP in the compound of general formula A, can be obtained. Other compounds represented by general formula A can be synthesized by the similar method.
1-3. As the hydrogen source at the synthesis of the compound of general formula B from the compound of general formula A, ammonium formate, cyclohexene or 1,4-cyclohexadiene can be used instead of hydrogen. As a solvent, lower alcohol such as methanol or ethanol, or ethyl acetate can be used. As a catalyst for hydrogenation, palladium on carbon catalyst, palladium hydroxide or Raney nickel can be used, and as the desirable one, palladium on carbon catalyst can be mentioned.
1-4. Mannich reaction can be carried out by using a combination of formalin, dimethylamine hydrochloride, acetic acid and sodium acetate, a combination of formalin with dimethylamine hydrochloride, a combination of formalin and diethylamine with acetic acid, a combination of formalin and inorganic acid e.g. hydrochloric acid with secondary amine e.g. pyrrolizine. As the desirable combination, the combination. of formalin, dimethylamine hydrochloride, acetic acid and sodium acetate can be mentioned.
2-1. The compound of general formula E used in the present invention can be obtained by reacting substituted aniline with para-toluenesulfonyl chloride (pTsCl) or methanesulfonyl chloride (MsCl) in dichloromethane in the presence of pyridine.
Instead of using pyridine in dichloromethane, it is possible to use M2CO3 (M is Na or K) in 1,4-dioxane/water mixed solvent.
2-2. The compound of general formula D can be synthesized from the compound of general formula E by Michael addition reaction to acrolein (2-10 equivalents) in alcohol e.g. methanol in which triethylamine (0.1-2 equivalents) exists, in approximately 100% yield.
In this case, tertiary alkylamine such as diisopropylethylamine, diazabicycloundecene or diazabicyclononen can be used instead of triethylamine.
2-3. Substituted dihydroquinoline represented by general formula F can be obtained by carrying out the cyclization reaction of the compound represented by general formula D in dichloromethane solution of trifluoromethanesulfonic acid or in tetrahydrofuran (THF) or 1,4-dioxane solution of hydrochloric acid or sulfuric acid.
2-4. The compound of general formula C, which is the aimed compound of the present invention, can be obtained by treating mentioned obtained compound of general formula F by heating (at approximately 50xc2x0 C. to 140xc2x0 C.) in dimethylsufoxide (DMSO) in which MOH (M is Na or K) exists.